- Email: [email protected]
Treatment of first-episode and prodromal signs
Management issues
Treatment of first-episode and prodromal signs
outreach to ensure engagement with services, making services ‘youth friendly’ and using a multidisciplinary biopsychosocial approach with emphasis on all aspects of recovery.2 Two systematic reviews have confirmed the relationship between long DUP and poor outcome,3,4 and two large randomized controlled trials (RCTs) have demonstrated the effectiveness of EI services in improving short- to medium-term outcomes in established FE.5–8 Besides facilitating recovery in FEP, EI services can also perform two other functions: treatment of at-risk (prodromal) mental states and early detection of psychosis in the community. In this article, we briefly review the evidence for prodromal intervention and early detection and highlight the principles of effective treatment of FEP.
Swaran P Singh Cristina Merino
Abstract The first episode of psychosis is now recognized as a critical period for effective intervention. There is also convincing evidence demonstrating the superiority of specialized early intervention services in improving short- to medium-term outcomes of the first episode of psychosis compared with standard care. There is now a concerted international research and clinical effort into identifying and treating ‘prodromal’ cases of psychosis. In this article, we describe the three different ways that early intervention can treat first-episode and prodromal cases (prodromal intervention, early detection and effective treatment of the first episode), summarizing the evidence for each of these strategies. We also outline the principles and ‘therapeutic ingredients’ of effective treatment of the first episode of psychosis.
Prodromal interventions Most patients who develop psychosis experience a long period of changes in behaviour, mood, cognition and functioning prior to the development of frank psychotic symptoms.9,10 Attenuated (subthreshold) psychotic symptoms and transient episodes of true psychosis that remit spontaneously (so-called BLIPS) are also common in the prodrome.11 However, prodromal symptoms are non-specific and have low predictive power in identifying true psychosis. Hence, the term ‘at-risk mental states’ is now commonly used instead of prodrome.12 The PACE (Personal Assessment and Crisis Evaluation) Clinic in Melbourne, Australia, has developed ‘ultra-high-risk’ criteria9 with 35–40% of those meeting these criteria developing a psychotic disorder within 12 months.13,14 The benefits of intervention at that early stage still remain unclear, and arguments have been made both for and against intervening in this group. Critics argue that lack of robust evidence for efficacy of prodromal interventions and the risk of stigmatizing and unnecessarily treating ‘false positives’ outweigh any putative advantages.15 Supporters claim that prodromal cases are already ‘help seeking’; therefore, ‘targeted’ rather than universal preventive strategies using ‘safe’ treatments such as low-dose antipsychotics and cognitive–behavioural therapy (CBT) are ethically and scientifically justified.16 Emerging evidence that brain changes may predate the onset of frank psychotic symptoms17 further strengthen the case for intervention in high-risk mental states. Although results are not conclusive, some evidence has emerged suggesting that intervention in high-risk mental states may delay, if not prevent, the onset of psychosis.18–20 Small sample sizes and lack of clarity about the relative contributions of medication and CBT in some trials suggest that it may be too early to start prodromal services in routine psychiatric care. High-risk/prodromal interventions continue to be an ethically challenging and clinically contentious area requiring further high-quality and methodologically robust research, and are therefore best provided in specialist centres.
Keywords antipsychotics; first-episode psychosis; prodrome; schizophrenia; treatment
Three important changes in mental health care provision have revolutionized the treatment of first-episode psychosis (FEP). These include evidence that the early years of emerging psychosis are critical in improving outcomes; the availability of second-generation antipsychotics; and the provision of care through specialized early intervention (EI) services, allowing the therapeutic pessimism associated with a diagnosis of psychosis to be replaced by cautious optimism. Although there was some early scepticism about the need for specialist services to provide care in FEP, evidence accumulated in the last decade has convincingly demonstrated the superiority of EI services in treating FEP compared with standard mental health care. Several EI models have been developed in the past two decades in Australia, New Zealand, Europe and North America.1 Despite differences in local mental health economies, EI services share certain common characteristics of ideology and function, such as ensuring a minimal delay between the emergence of psychosis and the start of effective treatment (duration of untreated psychosis; DUP), proactive
Swaran P Singh MBBS MD FRCPsych DM is a Professor of Social and Community Psychiatry at the University of Warwick and a Consultant Psychiatrist, EI Services, with the Birmingham and Solihull Mental Health Foundation Trust, UK. His research interests include early psychosis, health services evaluation, ethinicity and culture, mental health law and medical education. Conflicts of interest: none declared.
Early detection Pathways to care in early psychosis are complex and highly varied. A recent systematic review of pathways in FEP found that, besides delays in accessing help that occur because of a failure of carers and primary care services in recognizing emerging
Cristina Merino is a Staff Grade Psychiatrist, EI Services, with the Birmingham and Solihull Mental Health Foundation Trust, UK. Conflicts of interest: none declared.
PSYCHIATRY 7:11
467
© 2008 Elsevier Ltd. All rights reserved.
Management issues
sychosis, problems also occur within mental health services, p whereby individuals who develop psychosis while engaged with mental health services have delayed initiation of treatment for psychosis.21 Since long DUP is related to poor outcome, several strategies have been suggested to ensure earlier detection of cases in the community, including anti-stigma and community education campaigns, training of general practitioners and other individuals from key agencies (i.e. educational authorities, youth services and young offender programmes), information leaflets about local EI services, well-defined and well-publicized pathways into care and a proactive approach in suspected cases. There is some evidence that DUP can be reduced at a community level through intensive public education campaigns and provision of early detection teams.22,23 However, the effect of the education campaign may be temporary, with loss of any reduction in DUP when such campaigns are stopped.22 A community education programme in Canada24 found no significant reduction in DUP, and another study found that such campaigns manage to bring into treatment only those individuals with long DUPs who have previously been undetected.25
Principles of early intervention in psychosis • Reduce the time between onset of psychotic symptoms and initiation of effective treatment once the patient has been referred • Accelerate remission through effective biological and psychosocial interventions • Minimize an individual’s adverse reactions to the experience of psychosis • Maximize social and vocational functioning • Promote recovery during the early phase of the illness • Prevent relapse and treatment resistance • Develop meaningful therapeutic engagement early in the course of the disorder based on assertive outreach principles • Provide comprehensive assessment, treatment and rehabilitation in the least restrictive setting • Focus on carers’ needs and involve the family in a therapeutic alliance • Provide and run support groups for patients and carers • Ensure care is transferred thoughtfully and sensitively at the end of the treatment period
Treatment of first episode of psychosis
Table 1
Initial reports from the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne, Australia, suggested that EPPIC patients experienced better outcome with regard to overall quality of life and social functioning, had a lower average length of hospital stay and received lower mean doses of neuroleptics than non-EPPIC patients. The service appeared to be more costeffective than generic services, as the increased community costs of EPPIC were more than covered by reduced inpatient costs.26 Two large RCTs have since confirmed that EI services are more effective in improving short-term outcomes of FEP than standard care. In the UK, the specialized Lambeth Early Onset (LEO) service reduced readmissions and maintained better engagement with patients than standard care. LEO patients also had significantly better functional outcomes and greater adherence to medications at 18 month follow-up, although no marked improvement in symptoms was found.5,6 The OPUS trial in Denmark found similar favourable results for EI services in terms of treatment adherence and service satisfaction over 1 and 2 year follow-up together with a small effect on symptom reduction compared with standard psychiatric treatment.7 The OPUS trial concluded that an intensive EI programme improved clinical outcome after 2 years, but this improvement was not sustainable up to 5 years later.8 Effective treatment of established FEP is phase specific, with treatment strategies and interventions flexibly offered based on differing clinical needs as the disorder progresses. The principles of treatment in the early phases of psychosis are outlined in Table 1, and the therapeutic ingredients of such treatment are shown in Table 2.
therapeutic engagement. The best way to achieve this is by offering a multidisciplinary assessment in a low-stigma setting such as at home or at the general practice. The assessment should include, along with a detailed clinical level of functioning, quality of life, social and occupational needs and a detailed risk
Therapeutic ingredients of early intervention • Rapid and assertive response to first service contact with flexibility of appointment times • Primary treatment with atypical antipsychotic medication • Medication review and treatment ‘switching’ for treatmentintolerant or -resistant patients • Care designed to improve medication compliance • Standard side-effect assessment tools used routinely • Care coordinator-led psychosocial interventions such as psychoeducation, compliance therapy, relapse prevention and behavioural family intervention, etc. • Individual psychological treatments including individual cognitive–behavioural therapy • Individual early warnings signs and relapse prevention plan agreed and developed with patients and carers and available on file • Culturally sensitive and appropriate needs assessment • Comprehensive and documented risk assessment • Outreach visits by clinical team members • Care addresses all aspects of daily living • Educational and vocational recovery plan using principles of individual placement and support • Assessment and treatment of comorbidity, especially substance abuse, depression, suicidality and anxiety
The acute phase The key to successful management of the acute phase is to ensure a benign therapeutic start that engenders hope, minimizes stigma, avoids coercion as far as possible and promotes
PSYCHIATRY 7:11
Table 2
468
© 2008 Elsevier Ltd. All rights reserved.
Management issues
regarding what improvement to expect, when it will happen, possible side effects and modification of life-style issues such as alcohol and drug use, healthy diet and regular physical regular exercise.
a ssessment. Standardized assessment tools are particularly useful since these can be repeated to chart individual progress and also as measures of service evaluation. All patients should be assigned an individual care coordinator responsible for both providing and coordinating care. Individualized care plans need to be drawn up and agreed with the patient so that the care package is seen as consensual rather than coercive. The main aim of treatment in the acute phase is initiating antipsychotics to ensure a rapid symptomatic recovery. While some recent research27,28 shows similar efficacy of first- and second-generation antipsychotics – with the exception of clozapine, which has demonstrable superiority in treating treatment-resistant cases – the National Institute for Health and Clinical Guidance (NICE) guidelines29 in the UK recommend treatment with a lowdose second-generation antipsychotic (minimum effective dose within the therapeutic range), adjusted gradually according to response and tolerability and maintained at an adequate dosage for at least for 6–8 weeks before a change is considered. The clinical decision on drug choice is often driven by the sideeffect profile since there is no convincing evidence of differences in clinical efficacy between antipsychotics. For instance, drugs with a propensity towards weight gain and hyperglycaemia may be preferred less for young women or patients from the Indian subcontinent ancestry. Table 3 summarizes the side-effect profile of second-generation antipsychotics. Treatment with antipsychotics should continue for at least 12 months, following which medication may be gradually tapered in those who have made a complete recovery. Many patients with early psychosis are reluctant to take medication. An open and honest discussion offering information about the adverse consequences of untreated psychosis and repeated relapses, clinical benefits versus side-effect concerns and addressing the patient’s or family’s concerns promotes both therapeutic engagement and adherence to medication. It is good practice to discuss with the patient and family the most appropriate medication options, providing comprehensive information
Early recovery phase As the patient’s mental state is stabilized, the treatment plan needs to continue evolving to meet changing needs. There should be regular, structured and documented multidisciplinary reviews of care plans with the patient’s input to update needs and the plan itself. The aim in this phase is to help patients recover their premorbid level of function. Interventions include individual therapy, especially CBT, vocational assessment using principles of individual placement and support (IPS), assessment and management of comorbidity (especially substance misuse and depression, including early identification of hopelessness, pessimism or suicidal ideation), psychoeducation (for patients and carers) and behavioural family interventions. Continuing medication compliance is vital and rates of noncompliance tend to be high – up to 40–60% of the patients.30,31 There are multiple factors involved in poor compliance, including poor medication, subjective evaluation of side effects, insight, depression, social stigma, level of support and understanding provided by relatives and carers, illicit drugs use and poor therapeutic alliance between the patient and the team that provides care.32 Drug misuse, depression, poor medication efficacy and better cognitive performance at baseline are well-known predictors of poor compliance.33 There is some evidence that individualized interventions to identity and deal with these factors can improve the adherence to medication.34 Long-acting depot preparations should be considered early rather than wait for repeated relapses in patients poorly compliant with oral medication. Similarly, clozapine should be considered as soon as treatment resistance becomes obvious, such as after failure of treatment response to two different classes of antipsychotics.
Side effects of antipsychotics Side effects
Amisulpride
Aripiprazole
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Agranulocytosis Anticholinergic effects Cardiac EPS Hypertriglyceridaemia NMS Postural hypotension Prolactin elevation Sedation Seizures Tardive dyskinesia Weight gain
– – + + – ? + +++ – – – +
– – + –/+ – ? + – – – – –
+++ +++ +/++ – +++ + +++ – +++ +++ – +++
– + + –/+ +++ ? + + ++ – – +++
– + +/++ – ++ ? ++ – ++ – – ++
– – + + + + ++ +++ + – – ++
– – ++ –/+ – ? + + ++ – – –
EPS, extrapyramidal side effects; NMS, neuroleptic malignant syndrome. +++, high; ++, moderate; +, low; –, very low/zero; ?, data not available.
Table 3
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Management issues
8 Bertelsen M, Jeppesen P, Petersen L, et al. Five-year follow up of a randomized multicenter trial of intensive early intervention vs standard treatment for patients with a first episode of psychosis illness: the OPUS trial. Arch Gen Psychiatry 2008; 65: 762–71. 9 Häfner H, Nowotny B. Epidemiology of early-onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 1995; 245: 80–92. 10 Singh SP, Cooper JE, Fisher HL, et al. Determining the chronology and components of psychosis onset: the Nottingham Onset Schedule (NOS). Schizophr Res 2005; 80: 117–30. 11 Yung AR, McGorry PD. The initial prodrome in psychosis: descriptive and qualitative aspects. Aust N Z J Psychiatry 1996; 30: 587–99. 12 Yung AR, Yuen HP, McGorry PD, et al. Mapping the onset of psychosis: the comprehensive assessment of at-risk mental states. Aust N Z J Psychiatry 2005; 39: 964–71. 13 Yung AR, McGorry PO, Francey SM, et al. PACE: a specialised service for young people at risk of psychotic disorders. Med J Aust 2007; 187: s43–6. 14 Yung AR, Phillips LJ, Yuen HP, et al. Psychosis prediction: 12-month follow up of the high-risk (‘prodromal’) group. Schizophr Res 2003; 60: 21–32. 15 Warner R. Problems with early and very early intervention in psychosis. Br J Psychiatry Suppl 2005; 48: s104–7. 16 Yung AR, McGorry PD. Prediction of psychosis: setting the stage. Br J Psychiatry Suppl 2007; 51: s1–8. 17 Pantelis C, Velakoulis D, Wood SJ, et al. Neuroimaging and emerging psychotic disorders: the Melbourne ultra-high risk studies. Int Rev Psychiatry 2007; 19: 371–81. 18 McGorry PD, Yung AR, Phillips LJ, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to firstepisode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry 2002; 59: 2921–8. 19 McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, doubleblind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry 2006; 163: 790–9. 20 Ruhrmann S, Schultze-Lutter F, Maier W, Klosterkötter J. Pharmacological intervention in the initial prodromal phase of psychosis. Eur Psychiatry 2005; 20: 1–6. 21 Singh SP, Grange T. Measuring pathways to care in first-episode psychosis: a systematic review. Schizophr Res 2006; 81: 75–82. 22 Joa I, Johannessen JO, Auestad B, et al. The key to reducing duration of untreated first psychosis: information campaigns. Schizophr Bull 2008; 34: 466–72. 23 Melle I, Larsen TK, Haahr U, et al. Reducing the duration of untreated first-episode psychosis: effects on clinical presentation. Arch Gen Psychiatry 2004; 61: 143–50. 24 Malla A, Norman R, Scholten D, et al. A community intervention for early identification of first episode psychosis: impact on duration of untreated psychosis (DUP) and patient characteristics. Soc Psychiatry Psychiatr Epidemiol 2005; 40: 337–44. 25 Krstev H, Carbone S, Harrigan SM, et al. Early intervention in first-episode psychosis: the impact of a community development campaign. Soc Psychiatry Psychiatr Epidemiol 2004; 39: 711–19. 26 Mihalopoulos C, McGorry PD, Carter RC. Is phase-specific, community-oriented treatment of early psychosis an economically viable method of improving outcome? Acta Psychiatr Scand 1999; 100: 47–55. 27 Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on quality of life of second vs first generation antipsychotic drugs in schizophrenia. Cost Utility of the Latest
Consolidating recovery and discharge planning As recovery becomes established and enduring, the goals of treatment can shift to maximizing independence in housing, work/training area and leisure activities along with optimizing physical and mental well-being. Relapse-prevention strategies which involve identification of early warning signs are a very useful way of helping patients to gain insight into the illness and learning effective pathways back into care early, should the need arise. A proportion of patients who make a sustained and enduring recovery can be discharged to general practice, especially if they have come off medication. Although it is not clear how long a first-episode case should continue with an EI service, in the UK most EI services manage patients for about 3 years. Following this, patients who experience recurrent relapses, are taking clozapine or have ongoing needs for secondary care can be managed by community teams. A small proportion of chronically ill, severally disabled, high-risk or difficult to engage patients may need to have their care transferred to an assertive outreach team.
Conclusions The treatment provided by FEP services has been revolutionized by the recognition that there is a crucial window of opportunity in the first 2–3 years of the illness that is critical for effective intervention. A combination of service development in the form of specialist EI services, availability of new antipsychotics and evidence for the efficacy of therapies such as CBT in early psychosis have meant that service users and providers can feel hopeful about many first-episode patients living independently in the community. Prodromal interventions are a novel, challenging and exciting area of research and service development, although many ethical and clinical challenges remain. ◆
References 1 Edwards J, McGorry PD. Implementing early intervention in psychosis. London: Martin Dunitz, 2002. 2 Singh SP, Fisher HL. Early intervention in psychosis: obstacles and opportunities. Adv Psychiatr Treat 2005; 11: 71–8. 3 Marshall M, Lewis S, Lockwood A, et al. Association between duration of untreated psychosis and outcome in cohorts of firstepisode patients: a systematic review. Arch Gen Psychiatry 2005; 62: 975–83. 4 Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 2005; 162: 1785–804. 5 Craig TK, Garety P, Power P, et al. The Lambeth Early Onset (LEO) team: randomised controlled trial of the effectiveness of specialised care for early psychosis. BMJ 2004; 329: 1067. 6 Garety PA, Craig TK, Dunn G, et al. Specialised care for early psychosis: symptoms, social functioning and patient satisfactionrandomised controlled trial. Br J Psychiatry 2006; 188: 37–45. 7 Petersen L, Jeppesen P, Thorup A, et al. A randomised multicentre trial of integrated versus standard treatment for patients with a first episode of psychotic illness. BMJ 2005; 331: 602.
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Management issues
Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079–87. 28 Kahn RS, Fleischhacker WW, Bater H, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorders: an open randomized clinical trial. Lancet 2008; 371: 1085–97. 29 National Institute for Health and Clinical Excellence. Clinical Guideline 1. Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care. London: NICE, 2002. 30 Nose M, Barbui C, Tansella M. How often do patients with psychosis fail to adhere to treatment programmes? A systematic review. Psychol Med 2003; 33: 1149–60. 31 Young JL, Zonana HV, Shepler L. Medication noncompliance in schizophrenia: codification and update. Bull Am Acad Psychiatry Law 1986; 14: 105–22. 32 Barnes TR, Drake R. Pharmacological strategies for relapse prevention in schizophrenia. Psychiatry 2007; 6: 351–6. 33 Perkins DO, Gu G, Weiden PJ, et al. Predictors of treatment discontinuation and medication nonadherence in patients recovering
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from a first episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder: a randomised, double-blind, flexible-dose, multicenter study. J Clin Psychiatry 2008; 69: 106–13. 34 Hudson TJ, Owen RR, Thrush CR, et al. Guideline implementation and patient-tailoring strategies to improve medication adherence for schizophrenia. J Clin Psychiatry 2008; 69: 74–80.
Further reading Birchwood MJ, Fowler D, Jackson C (eds). Early Intervention in Psychosis: A Guide to Concepts, Evidence and Interventions. Oxford: Wiley Blackwell, 2000. French P, Morrison AP. Early Detection and Cognitive Therapy for People at High Risk of Developing Psychosis: A Treatment Approach. Oxford: Wiley Blackwell, 2004. Gleeson M, Mc Gorry PD (eds). Psychological Interventions in Early Psychosis: A Treatment Handbook. Oxford: Wiley Blackwell, 2004. Zipursky RB, Schulz SC (eds). The Early Stages of Schizophrenia. Arlington: American Psychiatric Press, 2001.
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© 2008 Elsevier Ltd. All rights reserved.
Treatment of first-episode and prodromal signs
outreach to ensure engagement with services, making services ‘youth friendly’ and using a multidisciplinary biopsychosocial approach with emphasis on all aspects of recovery.2 Two systematic reviews have confirmed the relationship between long DUP and poor outcome,3,4 and two large randomized controlled trials (RCTs) have demonstrated the effectiveness of EI services in improving short- to medium-term outcomes in established FE.5–8 Besides facilitating recovery in FEP, EI services can also perform two other functions: treatment of at-risk (prodromal) mental states and early detection of psychosis in the community. In this article, we briefly review the evidence for prodromal intervention and early detection and highlight the principles of effective treatment of FEP.
Swaran P Singh Cristina Merino
Abstract The first episode of psychosis is now recognized as a critical period for effective intervention. There is also convincing evidence demonstrating the superiority of specialized early intervention services in improving short- to medium-term outcomes of the first episode of psychosis compared with standard care. There is now a concerted international research and clinical effort into identifying and treating ‘prodromal’ cases of psychosis. In this article, we describe the three different ways that early intervention can treat first-episode and prodromal cases (prodromal intervention, early detection and effective treatment of the first episode), summarizing the evidence for each of these strategies. We also outline the principles and ‘therapeutic ingredients’ of effective treatment of the first episode of psychosis.
Prodromal interventions Most patients who develop psychosis experience a long period of changes in behaviour, mood, cognition and functioning prior to the development of frank psychotic symptoms.9,10 Attenuated (subthreshold) psychotic symptoms and transient episodes of true psychosis that remit spontaneously (so-called BLIPS) are also common in the prodrome.11 However, prodromal symptoms are non-specific and have low predictive power in identifying true psychosis. Hence, the term ‘at-risk mental states’ is now commonly used instead of prodrome.12 The PACE (Personal Assessment and Crisis Evaluation) Clinic in Melbourne, Australia, has developed ‘ultra-high-risk’ criteria9 with 35–40% of those meeting these criteria developing a psychotic disorder within 12 months.13,14 The benefits of intervention at that early stage still remain unclear, and arguments have been made both for and against intervening in this group. Critics argue that lack of robust evidence for efficacy of prodromal interventions and the risk of stigmatizing and unnecessarily treating ‘false positives’ outweigh any putative advantages.15 Supporters claim that prodromal cases are already ‘help seeking’; therefore, ‘targeted’ rather than universal preventive strategies using ‘safe’ treatments such as low-dose antipsychotics and cognitive–behavioural therapy (CBT) are ethically and scientifically justified.16 Emerging evidence that brain changes may predate the onset of frank psychotic symptoms17 further strengthen the case for intervention in high-risk mental states. Although results are not conclusive, some evidence has emerged suggesting that intervention in high-risk mental states may delay, if not prevent, the onset of psychosis.18–20 Small sample sizes and lack of clarity about the relative contributions of medication and CBT in some trials suggest that it may be too early to start prodromal services in routine psychiatric care. High-risk/prodromal interventions continue to be an ethically challenging and clinically contentious area requiring further high-quality and methodologically robust research, and are therefore best provided in specialist centres.
Keywords antipsychotics; first-episode psychosis; prodrome; schizophrenia; treatment
Three important changes in mental health care provision have revolutionized the treatment of first-episode psychosis (FEP). These include evidence that the early years of emerging psychosis are critical in improving outcomes; the availability of second-generation antipsychotics; and the provision of care through specialized early intervention (EI) services, allowing the therapeutic pessimism associated with a diagnosis of psychosis to be replaced by cautious optimism. Although there was some early scepticism about the need for specialist services to provide care in FEP, evidence accumulated in the last decade has convincingly demonstrated the superiority of EI services in treating FEP compared with standard mental health care. Several EI models have been developed in the past two decades in Australia, New Zealand, Europe and North America.1 Despite differences in local mental health economies, EI services share certain common characteristics of ideology and function, such as ensuring a minimal delay between the emergence of psychosis and the start of effective treatment (duration of untreated psychosis; DUP), proactive
Swaran P Singh MBBS MD FRCPsych DM is a Professor of Social and Community Psychiatry at the University of Warwick and a Consultant Psychiatrist, EI Services, with the Birmingham and Solihull Mental Health Foundation Trust, UK. His research interests include early psychosis, health services evaluation, ethinicity and culture, mental health law and medical education. Conflicts of interest: none declared.
Early detection Pathways to care in early psychosis are complex and highly varied. A recent systematic review of pathways in FEP found that, besides delays in accessing help that occur because of a failure of carers and primary care services in recognizing emerging
Cristina Merino is a Staff Grade Psychiatrist, EI Services, with the Birmingham and Solihull Mental Health Foundation Trust, UK. Conflicts of interest: none declared.
PSYCHIATRY 7:11
467
© 2008 Elsevier Ltd. All rights reserved.
Management issues
sychosis, problems also occur within mental health services, p whereby individuals who develop psychosis while engaged with mental health services have delayed initiation of treatment for psychosis.21 Since long DUP is related to poor outcome, several strategies have been suggested to ensure earlier detection of cases in the community, including anti-stigma and community education campaigns, training of general practitioners and other individuals from key agencies (i.e. educational authorities, youth services and young offender programmes), information leaflets about local EI services, well-defined and well-publicized pathways into care and a proactive approach in suspected cases. There is some evidence that DUP can be reduced at a community level through intensive public education campaigns and provision of early detection teams.22,23 However, the effect of the education campaign may be temporary, with loss of any reduction in DUP when such campaigns are stopped.22 A community education programme in Canada24 found no significant reduction in DUP, and another study found that such campaigns manage to bring into treatment only those individuals with long DUPs who have previously been undetected.25
Principles of early intervention in psychosis • Reduce the time between onset of psychotic symptoms and initiation of effective treatment once the patient has been referred • Accelerate remission through effective biological and psychosocial interventions • Minimize an individual’s adverse reactions to the experience of psychosis • Maximize social and vocational functioning • Promote recovery during the early phase of the illness • Prevent relapse and treatment resistance • Develop meaningful therapeutic engagement early in the course of the disorder based on assertive outreach principles • Provide comprehensive assessment, treatment and rehabilitation in the least restrictive setting • Focus on carers’ needs and involve the family in a therapeutic alliance • Provide and run support groups for patients and carers • Ensure care is transferred thoughtfully and sensitively at the end of the treatment period
Treatment of first episode of psychosis
Table 1
Initial reports from the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne, Australia, suggested that EPPIC patients experienced better outcome with regard to overall quality of life and social functioning, had a lower average length of hospital stay and received lower mean doses of neuroleptics than non-EPPIC patients. The service appeared to be more costeffective than generic services, as the increased community costs of EPPIC were more than covered by reduced inpatient costs.26 Two large RCTs have since confirmed that EI services are more effective in improving short-term outcomes of FEP than standard care. In the UK, the specialized Lambeth Early Onset (LEO) service reduced readmissions and maintained better engagement with patients than standard care. LEO patients also had significantly better functional outcomes and greater adherence to medications at 18 month follow-up, although no marked improvement in symptoms was found.5,6 The OPUS trial in Denmark found similar favourable results for EI services in terms of treatment adherence and service satisfaction over 1 and 2 year follow-up together with a small effect on symptom reduction compared with standard psychiatric treatment.7 The OPUS trial concluded that an intensive EI programme improved clinical outcome after 2 years, but this improvement was not sustainable up to 5 years later.8 Effective treatment of established FEP is phase specific, with treatment strategies and interventions flexibly offered based on differing clinical needs as the disorder progresses. The principles of treatment in the early phases of psychosis are outlined in Table 1, and the therapeutic ingredients of such treatment are shown in Table 2.
therapeutic engagement. The best way to achieve this is by offering a multidisciplinary assessment in a low-stigma setting such as at home or at the general practice. The assessment should include, along with a detailed clinical level of functioning, quality of life, social and occupational needs and a detailed risk
Therapeutic ingredients of early intervention • Rapid and assertive response to first service contact with flexibility of appointment times • Primary treatment with atypical antipsychotic medication • Medication review and treatment ‘switching’ for treatmentintolerant or -resistant patients • Care designed to improve medication compliance • Standard side-effect assessment tools used routinely • Care coordinator-led psychosocial interventions such as psychoeducation, compliance therapy, relapse prevention and behavioural family intervention, etc. • Individual psychological treatments including individual cognitive–behavioural therapy • Individual early warnings signs and relapse prevention plan agreed and developed with patients and carers and available on file • Culturally sensitive and appropriate needs assessment • Comprehensive and documented risk assessment • Outreach visits by clinical team members • Care addresses all aspects of daily living • Educational and vocational recovery plan using principles of individual placement and support • Assessment and treatment of comorbidity, especially substance abuse, depression, suicidality and anxiety
The acute phase The key to successful management of the acute phase is to ensure a benign therapeutic start that engenders hope, minimizes stigma, avoids coercion as far as possible and promotes
PSYCHIATRY 7:11
Table 2
468
© 2008 Elsevier Ltd. All rights reserved.
Management issues
regarding what improvement to expect, when it will happen, possible side effects and modification of life-style issues such as alcohol and drug use, healthy diet and regular physical regular exercise.
a ssessment. Standardized assessment tools are particularly useful since these can be repeated to chart individual progress and also as measures of service evaluation. All patients should be assigned an individual care coordinator responsible for both providing and coordinating care. Individualized care plans need to be drawn up and agreed with the patient so that the care package is seen as consensual rather than coercive. The main aim of treatment in the acute phase is initiating antipsychotics to ensure a rapid symptomatic recovery. While some recent research27,28 shows similar efficacy of first- and second-generation antipsychotics – with the exception of clozapine, which has demonstrable superiority in treating treatment-resistant cases – the National Institute for Health and Clinical Guidance (NICE) guidelines29 in the UK recommend treatment with a lowdose second-generation antipsychotic (minimum effective dose within the therapeutic range), adjusted gradually according to response and tolerability and maintained at an adequate dosage for at least for 6–8 weeks before a change is considered. The clinical decision on drug choice is often driven by the sideeffect profile since there is no convincing evidence of differences in clinical efficacy between antipsychotics. For instance, drugs with a propensity towards weight gain and hyperglycaemia may be preferred less for young women or patients from the Indian subcontinent ancestry. Table 3 summarizes the side-effect profile of second-generation antipsychotics. Treatment with antipsychotics should continue for at least 12 months, following which medication may be gradually tapered in those who have made a complete recovery. Many patients with early psychosis are reluctant to take medication. An open and honest discussion offering information about the adverse consequences of untreated psychosis and repeated relapses, clinical benefits versus side-effect concerns and addressing the patient’s or family’s concerns promotes both therapeutic engagement and adherence to medication. It is good practice to discuss with the patient and family the most appropriate medication options, providing comprehensive information
Early recovery phase As the patient’s mental state is stabilized, the treatment plan needs to continue evolving to meet changing needs. There should be regular, structured and documented multidisciplinary reviews of care plans with the patient’s input to update needs and the plan itself. The aim in this phase is to help patients recover their premorbid level of function. Interventions include individual therapy, especially CBT, vocational assessment using principles of individual placement and support (IPS), assessment and management of comorbidity (especially substance misuse and depression, including early identification of hopelessness, pessimism or suicidal ideation), psychoeducation (for patients and carers) and behavioural family interventions. Continuing medication compliance is vital and rates of noncompliance tend to be high – up to 40–60% of the patients.30,31 There are multiple factors involved in poor compliance, including poor medication, subjective evaluation of side effects, insight, depression, social stigma, level of support and understanding provided by relatives and carers, illicit drugs use and poor therapeutic alliance between the patient and the team that provides care.32 Drug misuse, depression, poor medication efficacy and better cognitive performance at baseline are well-known predictors of poor compliance.33 There is some evidence that individualized interventions to identity and deal with these factors can improve the adherence to medication.34 Long-acting depot preparations should be considered early rather than wait for repeated relapses in patients poorly compliant with oral medication. Similarly, clozapine should be considered as soon as treatment resistance becomes obvious, such as after failure of treatment response to two different classes of antipsychotics.
Side effects of antipsychotics Side effects
Amisulpride
Aripiprazole
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Agranulocytosis Anticholinergic effects Cardiac EPS Hypertriglyceridaemia NMS Postural hypotension Prolactin elevation Sedation Seizures Tardive dyskinesia Weight gain
– – + + – ? + +++ – – – +
– – + –/+ – ? + – – – – –
+++ +++ +/++ – +++ + +++ – +++ +++ – +++
– + + –/+ +++ ? + + ++ – – +++
– + +/++ – ++ ? ++ – ++ – – ++
– – + + + + ++ +++ + – – ++
– – ++ –/+ – ? + + ++ – – –
EPS, extrapyramidal side effects; NMS, neuroleptic malignant syndrome. +++, high; ++, moderate; +, low; –, very low/zero; ?, data not available.
Table 3
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8 Bertelsen M, Jeppesen P, Petersen L, et al. Five-year follow up of a randomized multicenter trial of intensive early intervention vs standard treatment for patients with a first episode of psychosis illness: the OPUS trial. Arch Gen Psychiatry 2008; 65: 762–71. 9 Häfner H, Nowotny B. Epidemiology of early-onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 1995; 245: 80–92. 10 Singh SP, Cooper JE, Fisher HL, et al. Determining the chronology and components of psychosis onset: the Nottingham Onset Schedule (NOS). Schizophr Res 2005; 80: 117–30. 11 Yung AR, McGorry PD. The initial prodrome in psychosis: descriptive and qualitative aspects. Aust N Z J Psychiatry 1996; 30: 587–99. 12 Yung AR, Yuen HP, McGorry PD, et al. Mapping the onset of psychosis: the comprehensive assessment of at-risk mental states. Aust N Z J Psychiatry 2005; 39: 964–71. 13 Yung AR, McGorry PO, Francey SM, et al. PACE: a specialised service for young people at risk of psychotic disorders. Med J Aust 2007; 187: s43–6. 14 Yung AR, Phillips LJ, Yuen HP, et al. Psychosis prediction: 12-month follow up of the high-risk (‘prodromal’) group. Schizophr Res 2003; 60: 21–32. 15 Warner R. Problems with early and very early intervention in psychosis. Br J Psychiatry Suppl 2005; 48: s104–7. 16 Yung AR, McGorry PD. Prediction of psychosis: setting the stage. Br J Psychiatry Suppl 2007; 51: s1–8. 17 Pantelis C, Velakoulis D, Wood SJ, et al. Neuroimaging and emerging psychotic disorders: the Melbourne ultra-high risk studies. Int Rev Psychiatry 2007; 19: 371–81. 18 McGorry PD, Yung AR, Phillips LJ, et al. Randomized controlled trial of interventions designed to reduce the risk of progression to firstepisode psychosis in a clinical sample with subthreshold symptoms. Arch Gen Psychiatry 2002; 59: 2921–8. 19 McGlashan TH, Zipursky RB, Perkins D, et al. Randomized, doubleblind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry 2006; 163: 790–9. 20 Ruhrmann S, Schultze-Lutter F, Maier W, Klosterkötter J. Pharmacological intervention in the initial prodromal phase of psychosis. Eur Psychiatry 2005; 20: 1–6. 21 Singh SP, Grange T. Measuring pathways to care in first-episode psychosis: a systematic review. Schizophr Res 2006; 81: 75–82. 22 Joa I, Johannessen JO, Auestad B, et al. The key to reducing duration of untreated first psychosis: information campaigns. Schizophr Bull 2008; 34: 466–72. 23 Melle I, Larsen TK, Haahr U, et al. Reducing the duration of untreated first-episode psychosis: effects on clinical presentation. Arch Gen Psychiatry 2004; 61: 143–50. 24 Malla A, Norman R, Scholten D, et al. A community intervention for early identification of first episode psychosis: impact on duration of untreated psychosis (DUP) and patient characteristics. Soc Psychiatry Psychiatr Epidemiol 2005; 40: 337–44. 25 Krstev H, Carbone S, Harrigan SM, et al. Early intervention in first-episode psychosis: the impact of a community development campaign. Soc Psychiatry Psychiatr Epidemiol 2004; 39: 711–19. 26 Mihalopoulos C, McGorry PD, Carter RC. Is phase-specific, community-oriented treatment of early psychosis an economically viable method of improving outcome? Acta Psychiatr Scand 1999; 100: 47–55. 27 Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on quality of life of second vs first generation antipsychotic drugs in schizophrenia. Cost Utility of the Latest
Consolidating recovery and discharge planning As recovery becomes established and enduring, the goals of treatment can shift to maximizing independence in housing, work/training area and leisure activities along with optimizing physical and mental well-being. Relapse-prevention strategies which involve identification of early warning signs are a very useful way of helping patients to gain insight into the illness and learning effective pathways back into care early, should the need arise. A proportion of patients who make a sustained and enduring recovery can be discharged to general practice, especially if they have come off medication. Although it is not clear how long a first-episode case should continue with an EI service, in the UK most EI services manage patients for about 3 years. Following this, patients who experience recurrent relapses, are taking clozapine or have ongoing needs for secondary care can be managed by community teams. A small proportion of chronically ill, severally disabled, high-risk or difficult to engage patients may need to have their care transferred to an assertive outreach team.
Conclusions The treatment provided by FEP services has been revolutionized by the recognition that there is a crucial window of opportunity in the first 2–3 years of the illness that is critical for effective intervention. A combination of service development in the form of specialist EI services, availability of new antipsychotics and evidence for the efficacy of therapies such as CBT in early psychosis have meant that service users and providers can feel hopeful about many first-episode patients living independently in the community. Prodromal interventions are a novel, challenging and exciting area of research and service development, although many ethical and clinical challenges remain. ◆
References 1 Edwards J, McGorry PD. Implementing early intervention in psychosis. London: Martin Dunitz, 2002. 2 Singh SP, Fisher HL. Early intervention in psychosis: obstacles and opportunities. Adv Psychiatr Treat 2005; 11: 71–8. 3 Marshall M, Lewis S, Lockwood A, et al. Association between duration of untreated psychosis and outcome in cohorts of firstepisode patients: a systematic review. Arch Gen Psychiatry 2005; 62: 975–83. 4 Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 2005; 162: 1785–804. 5 Craig TK, Garety P, Power P, et al. The Lambeth Early Onset (LEO) team: randomised controlled trial of the effectiveness of specialised care for early psychosis. BMJ 2004; 329: 1067. 6 Garety PA, Craig TK, Dunn G, et al. Specialised care for early psychosis: symptoms, social functioning and patient satisfactionrandomised controlled trial. Br J Psychiatry 2006; 188: 37–45. 7 Petersen L, Jeppesen P, Thorup A, et al. A randomised multicentre trial of integrated versus standard treatment for patients with a first episode of psychotic illness. BMJ 2005; 331: 602.
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Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079–87. 28 Kahn RS, Fleischhacker WW, Bater H, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorders: an open randomized clinical trial. Lancet 2008; 371: 1085–97. 29 National Institute for Health and Clinical Excellence. Clinical Guideline 1. Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care. London: NICE, 2002. 30 Nose M, Barbui C, Tansella M. How often do patients with psychosis fail to adhere to treatment programmes? A systematic review. Psychol Med 2003; 33: 1149–60. 31 Young JL, Zonana HV, Shepler L. Medication noncompliance in schizophrenia: codification and update. Bull Am Acad Psychiatry Law 1986; 14: 105–22. 32 Barnes TR, Drake R. Pharmacological strategies for relapse prevention in schizophrenia. Psychiatry 2007; 6: 351–6. 33 Perkins DO, Gu G, Weiden PJ, et al. Predictors of treatment discontinuation and medication nonadherence in patients recovering
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from a first episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder: a randomised, double-blind, flexible-dose, multicenter study. J Clin Psychiatry 2008; 69: 106–13. 34 Hudson TJ, Owen RR, Thrush CR, et al. Guideline implementation and patient-tailoring strategies to improve medication adherence for schizophrenia. J Clin Psychiatry 2008; 69: 74–80.
Further reading Birchwood MJ, Fowler D, Jackson C (eds). Early Intervention in Psychosis: A Guide to Concepts, Evidence and Interventions. Oxford: Wiley Blackwell, 2000. French P, Morrison AP. Early Detection and Cognitive Therapy for People at High Risk of Developing Psychosis: A Treatment Approach. Oxford: Wiley Blackwell, 2004. Gleeson M, Mc Gorry PD (eds). Psychological Interventions in Early Psychosis: A Treatment Handbook. Oxford: Wiley Blackwell, 2004. Zipursky RB, Schulz SC (eds). The Early Stages of Schizophrenia. Arlington: American Psychiatric Press, 2001.
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